300. Adenoviral Delivery of the Gene Encoding Secretable Trimeric TRAIL Induces Apoptosis and Suppresses Human Malignant Glioma In Vivo

Malignant gliomas are most common human primary brain tumors. Despite of intensive research, current treatments have not significantly improved patient survival over last three decades. TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a wide range of tumor cells without fatal effect on normal cells. In previous study, we designed a replication deficient adenovirus (Ad) to encode secretable trimeric TRAIL (stTRAIL). This adenovirus (Ad-stTRAIL) potently induced apoptosis in vivo and in vitro by stTRAIL secreted from infected tumor cells. As an approach to Ad-stTRAIL mediated cancer gene therapy, we found out the tumoricidal effects of Ad-stTRAIL in several human malignant glioma cell lines in vitro. In murine xenograft model bearing human malignant glioma U-87MG cell line, the intratumoral administration of Ad-stTRAIL exerted the significant suppression of tumor growth and histological analysis revealed that Ad-stTRAIL regressed tumor growth by inducing apoptotic cell death. In murine brain tumor model implanted U87-MG intracranially through stereotactics, the intratumoral and intracranial administration of Ad-stTRAIL prolonged the survival of mice and reduced the tumor volume in the absence of any acute and delayed neurotoxicity. Contrary to rapid clearance of systemically delivered recombinant TRAIL protein, Ad-stTRAIL showed the persistent expressed stTRAIL level and suppressed the tumor more significantly. Furthermore, we found out that Ad-stTRAIL and combination with chemotherapeutic agents reinforced the potential of Ad-stTRAIL overcoming the TRAIL resistance of certain glioma cell lines. These results suggest that Ad-stTRAIL shows its potential feature as a mean of treating human malignant glioma